Method for the preparation of sulfathiazoles



Patented Sept. 20, 1949 DIETHOD FOR THE PREPARATION OF .SULFATHIAZOLES Michael N. Dvornikoff, St. Louis, Mo., assignor to Monsanto Chemical Company, St. Louis, Mo., a

corporation of Delaware No Drawing. Application June 23, 1944, Serial No. 541,849

7 Claims.

This invention relates to the preparation of sulfa drugs and in particular to the syn-theses of new 4-thiazoline derivatives and a process of preparing sulfathiazole therefrom.

An object of the invention is to provide novel 4-thiazoline derivatives which are useful in themselves as therapeutic agents and as intermediates for the preparation of sulfathiazole.

Another object of the invention is to provide a process for preparing novel l-thiazoline derivatives which are useful as therapeutic agents and as intermediates for the preparation of sulfathiazole.

A further object of the invention is to provide a novel process for preparing sulfathiazole.

Other objects will become apparent from the following description and examples.

The present invention, generally stated, comprises reacting Z-aminothiazole in aqueous solution in the presence of an alkaline agent, such as sodium bicarbonate or sodium carbonate, with an acyl benzene sulfonyl halide 'haVing the formula:

I 11.0 onOs 0:.Hal

in which R.CO represents an acyl radical, such as the acetyl, butyryl and benzoyl and hexahydrobenzoyl radicals. The reactants may be added to the aqueous reaction medium in the form of dry materials or in the form of Wet materials, such as aqueous slurries or pastes. The fact that water wet acyl sulfanilyl halides may be used is of particular advantage, since it eliminates the drying operation together With the cost of that operation in time and materials. Moreover, the Z-aminothiazole may be employed as the hydrohalide, for example, the hydrochloride or hydrobromide, in which instance the free Z-aminothiazole is liberated by adding an alkali, such as sodium bicarbonate or sodium carbonate to the aqueous solution before adding the N -acyl sulfanilyl halide. The solid product of the reaction is separated from the reaction mixture, washed with water and dried. The product is a 2-imino-3- (N -acyl-sulfanilyl) -4-thiazoline having the formula:

The product may also be called 2-imino-3-(N acyl-sulfanilyl)-2,3-dihydrothiazole. The products isolated from the reaction mixtures are white powders which may be useful for their activity against various micro-organisms and also as intermediates in the preparation of other therapeutic agents, such as sulfathiazole.

As a further embodiment of the present invenzen-239.6)

tion, the thiazoline derivatives hereinbefore described when heated are converted to the corresponding 2-(N -acyl-sulfanily1) thiazoles havin the formula:

I ll aoorrOsonv-r': OH

presence of an alkaline agent such as sodium bicarbonate or sodium carbonate. The solid product of the reaction is separated from the reaction mixture, washed with water and dried. The product obtained is Z-imino-B-acetyl-sulfanilyl- 4-thiazoline having the formula: a

' cn=on When the above product is melted and heated, for example in vacuum at approximately 160 C.,

a reaction takes place substantiall without the loss of weight of the starting product, and the reaction product is N -acetylsulfathiazole, having the formula:

The N -acetylsulfathiazole product can then be hydrolyzed to remove the acetyl residue with the resultantiormation-of sulfathiazole. As an alternative; the novel product, 2-imino-3-acetylsulfanilyll-thiazoline may be heated in dry pyridine to approximately 75 C. for about one hour. The product resulting from this treatment is again N -acetylsul'fathiazole. The addition of a quantity of acetylsulfanilyl chloride to the dry pyridine solution tends to increase the yield of N -acetylsulfathiazole.

The aforedescribed process is distinguished from the process commonly employed to prepare sulfathiazole and which comprises reacting anhydrous Z-aminothiazol with anhydrous acetylsulfanilyl chloride in anhydrous pyridine. Such a process produces Z-acetylsulfathiazole which is subsequently hydrolyzed to suliathiazole. Applicants discovery. of thenovel thiazoline derivative and a methodfoipreparing thegsamehtogether with a method for preparing sulfathiazole obviates the necessity of preparing anhydrous acyl sulfanilyl halides and permits the,utilization,of aminothiazole in the form of its salt.

The following examples are provided to i1lus-' trate the novel features of thei'invention.,.a.Theseae examples are to be construed-merely assillusatrative of the invention and not as limiting the invention to the particular reaction;-conditions. described therein.

Example I One-tenth mole of 2-aminothiazole is dissolved in=1150 cc: of=wateri Thesolution;may;be-treated-a: with'icharcoalvand. .is then; filtered; Toithezrfi tratei is. Eaddedsin': smallzayportionssmllfi 311101830 acetylsulfanilyl chloride and 0.140 mole of;sodiung.;; bicarbonate. While the addition is being made, the solution, is agitated and "maintained at a temperature of about 5-10-C. One-fourth of the acetylsulfanilyl chloride is introduced in 30 minutes; and-themthe bicarbonate andtheremaining acetylsulianilyl chlorideare:addedswithinaperiod of :1itor2 hours:.-=.-- The mixture is stirred atabout 510i.C.; .for. tWQahOHlSg and-the -stirr=ing'. isl oo tinned at. :room .temperature -;for ,;a-b,out ='.l0 hours longer until ,-:all acety1su1f anilyl: chloride;j=; is ;re acted; i: The. solid-product of -.the--;reaqtion,-issep arated {by filtration; washedwith -;water,- andr the filter cakeis sucked zas;dry as.apossiblefand driedw, at room. temperature Thec-yield of 2-.im-ino- 3.- acetylsulranilyl#I-thiazolines is .28 g. 94%- .of the in theoretical amount 2 bascdjzso -..1-2aminothiazole;.i based-gen .acetylsulfanilylaychloride) The? product is :3 white .powder whichf'npon heating r; forms N racetyisuliathiazoleav Exam II' 4 0 Example III Fifteen gramswof 2-imino-3-acety1sulfani1y1- 4-thiazoline,.prepared according tothe process of Example I, were melted and heated in vacuum at 160 C. No loss in weight was observed. The reaction product was subjected.-.'to alkaline-hm, drolysis: which yielded crude sulfathiazole,- M.-1P.r 134}-;C...(10.0 g. ;;78% yield). The purifiedsulfa-a thiazolemeltedat198%0; (7.0 g; g .54 -yield,based onthe thiazoline)-.-

Example I V A mixture-0f. .29.'7 grams (0.1. .mole). l-of r edl i- 6 azoline derivativa' repared according to Example I, and-45cc:-:of dry-pyridinewas maintained at;

C. for 1 hour. N -acetylsulfathiazolewas obtaineds-in 'l5 yield. This-product uponhydroly 4. chloride .wasamaintainedat 75l, C. =fo r -1 hour. N -z-acetylsuljathiazole wasgabt'a-ined 8,8 yield. This product was subsequently hydrolyzed to provide. crude sulfathiazole.

Example VI The process of Example I was repeated, using 35 ;Je-g. f;Nf*&butyryl; sulfanilyl bromide and 10.0 g. of .'.2:-.aminothiaZQlQ:'v The resulting product was WZ-im-inQ-Be(Ni butyrylsulfanilyl) -4 thiazoline.

Thisgproductflmayhbe used as a pharmaceutical or may jpeheatedin pyridine or alone according to the methods of Examples III and IV to form the corresponding N -butyry1 sulfathiazole which in turn may be hydrolyzed to form sulfathiazole.

Example VII in which RCO represents an acyl radicalunting conversion to the corresponding N -acylsulfathiazole is complete.-.-,,

2. A process of preparing N -acylsulfathiazole whi h qm ris sr heatin .ananhy rous 3- fiN- H acy'lsulfanilylh-2-imino-=thiazoline having ,vthe g f0rmu1ar.-.-.-

E noolrmO som; 5

CH: .H

in-iwhich BBQ 2 represents an. acyl; .radipa1 zat; about l60"C..'untiL conversion to the;- ,COI'IGSDOD-drfi ing .Nieacylsuliathia-zole is complete.

3. 5A process 1 of preparing .an;.- N :-acy1Sulfa-.-=:.- thiazole which comprises .:heatingan anhydrous1+;v 3- (Nf acylsulfanilyh) -.Z-imino-4-thiazoline. rhavnvs. ing-zthezzformulacw in which R.CO represents an acyl radical-,'-in=an-'- hydrous pyridine at about 75 C. until conversion to the corresponding N -acylsulf athiazole is com- 5 plete.

4. A process of preparing. N -acetylsulfathiazole which comprises heating an anhydrous 3-(N aeetylsmfanilyl) 42+imino 4-thiazolinemun-i tilconversion to -N acety1sulfathiaz0le is comets. plete.-

5. A process of :.-.'prepari=ng a N acetylsulfa' s. thiazolewhich comprises! heating: ananhydrous =e 3- N acetylsulfanilyl)QZ iminO-FL-I thiazolinewatm about C. until 'conversion=to N acetylsulia thiazoleiiscom1plete;

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS 6 FOREIGN PATENTS Number Country Date 113,723 Australia Sept. 4, 1941 216,425 Switzerland Oct. 1, 1940 517,272 Great Britain Jan. 25, 1940 533,495 Great Britain Feb. 14, 1941 848,175 France July 17, 1939 OTHER REFERENCES Serial No. 334,990, Fololi (A. P. C.) pub. Apr. 20, 1943.

Chemical Reviews, Aug. 1940, pages 108-109, 152 and 187-189.

Helv. Chim. Acta, May 2, 1941, pp. 536-538.

Journal Amer. Chem. 800., Oct. 1941, pp, 2739-2740.

Journal Amer. Chem. 800., Nov. 1942, pp. 2532-2537.

Journal Amer. Chem. Soc, Feb. 1943, pp. 156- Number Name Date 2,097,414 Kharasch Oct. 26, 1937 2,362,037 Newberry Nov. 7, 1944 20 159.

Certificate of Correction September 20, 1949 Patent No. 2,482,085

MICHAEL N. DVORNIKOFF certified that error appears in the printed specification of the above t requiring correction as follows:

Examples V1 and V read Examples 1V should be read with this correction the Patent Oflice. A. D. 1950.

It is hereby numbered paten Column 4, line 23, for

and that the said Letters Patent same may conform to the record of the case in Signed and sealed this 7th day of February,

and V; therein that the THOMAS F. MURPHY,

Assistant Commissioner of Patents. 

